期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 1, 页码 264-274出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.495499
关键词
Dopamine; Dopamine Transporters; Drug Action; Electrophysiology; Transgenic Mice; Amperometry; Cocaine; Microdialysis; Striatum
资金
- Progetto Finalizzato Strategico
- National Institute of Mental Health [MH086545]
- G. Harold and Leila Y. Mathers Charitable Foundation
We combined in vitro amperometric, optical analysis of fluorescent false neurotransmitters and microdialysis techniques to unveil that cocaine and methylphenidate induced a marked depression of the synaptic release of dopamine (DA) in mouse striatum. In contrast to the classical dopamine transporter (DAT)-dependent enhancement of the dopaminergic signal observed at concentrations of cocaine lower than 3 m, the inhibitory effect of cocaine was found at concentrations higher than 3 m. The paradoxical inhibitory effect of cocaine and methylphenidate was associated with a decrease in synapsin phosphorylation. Interestingly, a cocaine-induced depression of DA release was only present in cocaine-insensitive animals (DAT-CI). Similar effects of cocaine were produced by methylphenidate in both wild-type and DAT-CI mice. On the other hand, nomifensine only enhanced the dopaminergic signal either in wild-type or in DAT-CI mice. Overall, these results indicate that cocaine and methylphenidate can increase or decrease DA neurotransmission by blocking reuptake and reducing the exocytotic release, respectively. The biphasic reshaping of DA neurotransmission could contribute to different behavioral effects of psychostimulants, including the calming ones, in attention deficit hyperactivity disorder.
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